| Summary: | 碩士 === 國立成功大學 === 臨床藥學研究所 === 97 === Introduction
Cytochrome P450 3A (CYP3A) is an important subfamily of drug- metabolizing enzymes. In humans, it is responsible for metabolizing numerous drugs across several therapeutic classes. Interindividual variability in the expression and activity of CYP3A is considerable, and may be responsible for variability in drug response. The use of probe substrates is a widely accepted method for evaluating the activity of cytochrome P450 (CYP) enzymes in individuals. Mosapride, a new prokinetic agent, was evaluated as an in vivo probe for measuring hepatic CYP3A activity in rats. However, the metabolism of orally administrated mosapride involves the combination of gastrointestinal and hepatic CYP3A activity. Whether mosapride can be used as a CYP3A probe under such circumstance is of great interest.
Purpose
The objective of this study was to evaluate the suitability of limited sampling strategy to predict AUC of CYP3A phenotyping probe mosapride in rats following oral administration.
Methods
In control groups, male rats received mosapride（10、20、30、40、50 mg/kg）orally and a female control group (10mg/kg) was also included for studying its pharmacokinetics. And in the CYP3A- modulation group, male rats received 10 mg/kg mosapride after pretreatment with ketoconazole (inhibitor). The plasma concentrations of mosapride were followed for up to 480 or 720 min, and the kinetic parameters were estimated by non-compartment analysis. The contents of CYP 3A2 in hepatic and intestinal microsomes of rats were measured by western blotting analysis.
Results
Describing by well-stirred model, the hepatic and intestinal microsomes CYP3A2 contents showed strong correlation with mosapride oral clearance (r=0.7635，p<0.0001). Therefore, mosapride oral clearance can be used to reflect the in vivo CYP3A activity. Based on the data of control and CYP3A modulation group, limited sampling strategies were derived, validated, and evaluated for its applicability. It was demonstrated that the AUC of mosapride can be well predicted by the concentration of few time points.
Conclusion
Few time points of plasma concentrations after orally administrated mosapride was needed to precisely predict its AUC and hence clearance in rats. Therefore, this approach represents an effective method for assessing in vivo CYP3A activity.
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